Article ; Online: Analgesic effects of the cathepsin K inhibitor L-006235 in the monosodium iodoacetate model of osteoarthritis pain.
Pain reports
2018 Volume 3, Issue 6, Page(s) e685
Abstract: ... pain lead us to investigate the effects of L-006235, a potent and selective inhibitor of cathepsin K ... 100 mg/kg) and therapeutic (100 mg/kg) oral dosing with L-006235 on weight-bearing asymmetry, hind paw ... in the monosodium iodoacetate rat model of OA pain.: Results: Preventative L-006235 inhibited weight-bearing ...
Abstract | Introduction: The mounting evidence that osteoclasts play an important role in osteoarthritis (OA) pain lead us to investigate the effects of L-006235, a potent and selective inhibitor of cathepsin K, on pain behaviour and joint pathology in a model of OA pain. Methods: Effects of preventative (30 and 100 mg/kg) and therapeutic (100 mg/kg) oral dosing with L-006235 on weight-bearing asymmetry, hind paw withdrawal thresholds, cartilage and bone pathology, synovial inflammation, and drug exposure were studied in the monosodium iodoacetate rat model of OA pain. Results: Preventative L-006235 inhibited weight-bearing asymmetry from day 14, with this measure nearly abolished by the higher dose. In the same treatment setting, L-006235 prevented lowering of hind paw withdrawal thresholds from day 7. Exposure to L-006235 in plasma was higher for the 100 mg/kg dose, compared with 30 mg/kg. Therapeutic dosing with L-006235 from day 14 significantly inhibited weight-bearing asymmetry, compared with monosodium iodoacetate vehicle rats. Regression analysis revealed a significant interaction coefficient of the effects of L-006235 on weight-bearing asymmetry and synovitis score, but not for cartilage damage nor osteophyte scores. Conclusion: Our novel finding that cathepsin K inhibition is analgesic in a clinically relevant model of OA pain provides new evidence for the therapeutic potential of this target. |
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Language | English |
Publishing date | 2018-10-05 |
Publishing country | United States |
Document type | Journal Article |
ISSN | 2471-2531 |
ISSN (online) | 2471-2531 |
DOI | 10.1097/PR9.0000000000000685 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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